Simvastatin attenuates the endothelial pro-thrombotic shift in saphenous vein grafts induced by Advanced glycation endproducts

Cristiano Spadaccio, Federico De Marco, Fabio Di Domenico, Raffaella Coccia, Mario Lusini, Raffaele Barbato, Elvio Covino, Massimo Chello

Research output: Contribution to journalArticle

Abstract

Background Advanced glycation endproducts (AGEs) and its receptors (RAGEs) are heterogeneous signaling proteins associated to diabetes and responsible of endothelial alterations leading to atherosclerosis progression and graft failure. The aim of this study was to investigate the role of statin in reducing AGEs related endothelial damage. Methods Endothelial cell(EC) obtained from leftovers of saphenous vein grafts of non-diabetic patients were incubated with AGEs (2 and 20 μM) and subsequently treated with Simvastatin. Neutrophils (PNM) adherence, ROS production and RAGE and peroxisome proliferator-activated receptors-gamma (PPAR-γ) expression were analyzed. As clinical validation of the in vitro findings, ECs of diabetic patients in optimized glycaemic control administered with a 3 weeks Simvastatin regimen were similarly processed. Results Simvastatin blunted the rise in PMN adhesion and ROS generation following stimulation of saphenous vein EC culture with AGEs in vitro. This effect was time dependent and was associated to an increase in PPAR-γ induction paralleled by a decrease in RAGEs expression. Parallely, data from diabetic patients administered with Simvastatin showed a similar significant reduction in PNM adhesion and ROS generation. Simvastatin treatment significantly decreased RAGEs expression in ECs from diabetic patients and determined a slight increase in PPAR-γ expression but the latter failed to reach statistical significance. Interference in the function of these two crucial pathways might be at the root of the statin antinflammatory and antithrombotic effect in the context of AGEs-associated damage. Conclusions Despite the recently raised warning on the use of statins in the diabetic population, this study elucidates their cornerstone position in endothelial homeostasis of saphenous grafts in patients with controlled diabetes.

Original languageEnglish
Pages (from-to)418-425
Number of pages8
JournalThrombosis Research
Volume133
Issue number3
DOIs
Publication statusPublished - Mar 2014

Fingerprint

Simvastatin
Saphenous Vein
Hydroxymethylglutaryl-CoA Reductase Inhibitors
PPAR gamma
Transplants
Endothelial Cells
Atherosclerosis
Neutrophils
Homeostasis
Cell Culture Techniques
Population
Proteins

Keywords

  • Advanced Glycation Endproducts
  • CABG
  • Diabetes Mellitus
  • Graft failure
  • Saphenous graft

ASJC Scopus subject areas

  • Hematology
  • Medicine(all)

Cite this

Simvastatin attenuates the endothelial pro-thrombotic shift in saphenous vein grafts induced by Advanced glycation endproducts. / Spadaccio, Cristiano; De Marco, Federico; Di Domenico, Fabio; Coccia, Raffaella; Lusini, Mario; Barbato, Raffaele; Covino, Elvio; Chello, Massimo.

In: Thrombosis Research, Vol. 133, No. 3, 03.2014, p. 418-425.

Research output: Contribution to journalArticle

Spadaccio, Cristiano ; De Marco, Federico ; Di Domenico, Fabio ; Coccia, Raffaella ; Lusini, Mario ; Barbato, Raffaele ; Covino, Elvio ; Chello, Massimo. / Simvastatin attenuates the endothelial pro-thrombotic shift in saphenous vein grafts induced by Advanced glycation endproducts. In: Thrombosis Research. 2014 ; Vol. 133, No. 3. pp. 418-425.
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AU - Spadaccio, Cristiano

AU - De Marco, Federico

AU - Di Domenico, Fabio

AU - Coccia, Raffaella

AU - Lusini, Mario

AU - Barbato, Raffaele

AU - Covino, Elvio

AU - Chello, Massimo

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N2 - Background Advanced glycation endproducts (AGEs) and its receptors (RAGEs) are heterogeneous signaling proteins associated to diabetes and responsible of endothelial alterations leading to atherosclerosis progression and graft failure. The aim of this study was to investigate the role of statin in reducing AGEs related endothelial damage. Methods Endothelial cell(EC) obtained from leftovers of saphenous vein grafts of non-diabetic patients were incubated with AGEs (2 and 20 μM) and subsequently treated with Simvastatin. Neutrophils (PNM) adherence, ROS production and RAGE and peroxisome proliferator-activated receptors-gamma (PPAR-γ) expression were analyzed. As clinical validation of the in vitro findings, ECs of diabetic patients in optimized glycaemic control administered with a 3 weeks Simvastatin regimen were similarly processed. Results Simvastatin blunted the rise in PMN adhesion and ROS generation following stimulation of saphenous vein EC culture with AGEs in vitro. This effect was time dependent and was associated to an increase in PPAR-γ induction paralleled by a decrease in RAGEs expression. Parallely, data from diabetic patients administered with Simvastatin showed a similar significant reduction in PNM adhesion and ROS generation. Simvastatin treatment significantly decreased RAGEs expression in ECs from diabetic patients and determined a slight increase in PPAR-γ expression but the latter failed to reach statistical significance. Interference in the function of these two crucial pathways might be at the root of the statin antinflammatory and antithrombotic effect in the context of AGEs-associated damage. Conclusions Despite the recently raised warning on the use of statins in the diabetic population, this study elucidates their cornerstone position in endothelial homeostasis of saphenous grafts in patients with controlled diabetes.

AB - Background Advanced glycation endproducts (AGEs) and its receptors (RAGEs) are heterogeneous signaling proteins associated to diabetes and responsible of endothelial alterations leading to atherosclerosis progression and graft failure. The aim of this study was to investigate the role of statin in reducing AGEs related endothelial damage. Methods Endothelial cell(EC) obtained from leftovers of saphenous vein grafts of non-diabetic patients were incubated with AGEs (2 and 20 μM) and subsequently treated with Simvastatin. Neutrophils (PNM) adherence, ROS production and RAGE and peroxisome proliferator-activated receptors-gamma (PPAR-γ) expression were analyzed. As clinical validation of the in vitro findings, ECs of diabetic patients in optimized glycaemic control administered with a 3 weeks Simvastatin regimen were similarly processed. Results Simvastatin blunted the rise in PMN adhesion and ROS generation following stimulation of saphenous vein EC culture with AGEs in vitro. This effect was time dependent and was associated to an increase in PPAR-γ induction paralleled by a decrease in RAGEs expression. Parallely, data from diabetic patients administered with Simvastatin showed a similar significant reduction in PNM adhesion and ROS generation. Simvastatin treatment significantly decreased RAGEs expression in ECs from diabetic patients and determined a slight increase in PPAR-γ expression but the latter failed to reach statistical significance. Interference in the function of these two crucial pathways might be at the root of the statin antinflammatory and antithrombotic effect in the context of AGEs-associated damage. Conclusions Despite the recently raised warning on the use of statins in the diabetic population, this study elucidates their cornerstone position in endothelial homeostasis of saphenous grafts in patients with controlled diabetes.

KW - Advanced Glycation Endproducts

KW - CABG

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KW - Graft failure

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